6.5. Overview of Proposed Genetics, Genomics and Molecular Resource Core (RC-2) Activities: 6.5.a) Specific Aims: The purpose of RC-2 is to provide the human resources, infrastructure, and training necessary to facilitate the highest quality contemporary biological studies related to frailty, the overall focus of the Hopkins OAIC. The resources provided by this core to frailty researchers will include 1) leading interdisciplinary expertise for the design and implementation of molecular, genetic and genomic studies related to frailty; 2) access to state-of-the-art genetic, genomic and molecular technologies; 3) access to a diversity of human and frail animal model DNA, tissue and serum samples; 4) mentorship and training in genetics, genomics, and molecular biology; and 5) expertise to help translate molecular, genetic and genomic findings to clinically meaningful interventions. By providing these intellectual and physical resources, RC-2 will facilitate the elucidation of clinically relevant biological pathways that underlie frailty and related biological vulnerability, and thereby identify promising targets toward which to develop interventions that prevent or attenuate frailty. The first years of RC-2 funding have produced significant progress towards these goals through: the establishment of state-of-the-art infrastructure for genetic data generation and analyses related to frailty; the assemblage of a highly-skilled multidisciplinarv team of experienced investigators; and important scientific progress related to frailty, including the development of novel endophenotypes, the identification of critical molecular pathways associated with frailty, and the development of a frail mouse model. As a result of this progress, RC-2 and its leadership has become a national resource for the development of frailty and agingrelated genetics research as measured by publications, award-winning national symposia, consortium building efforts for combining populations of older adults, development and funding of collaborative genetics studies with investigators across the country, and provision of training and mentorship for the next generation of investgators interested in studying the molecular and genetic basis of frailty and its translation into clinical care. Although RC-2 sponsored investigators have made substantial scientific progress and have resolved many initial resource challenges, the next stages of basic investigation of frailty require resolution of newly identified challenges in order to test novel hypotheses originating from data generated in the first cycle of funding. To address these challenges, and to test the next generation of hypotheses related to frailty, we propose to expand the scope of RC-2 beyond human genetics studies into a comprehensive genetics, genomics, and molecular core that builds on the evolving science, infrastructure, and expertise developed in the first years of this center. This evolution will require the leveraging of additional human and infrastructure resources from across the Johns Hopkins Medical Institutions towards frailty research, and include facilitating access to senior leaders with necessary expertise and infrastructure to a) facilitate analytical strategies needed to analyze the vast amounts of genetics and genomics data being generated, b) incorporate measurements of oxidative stress, mitochondria! function, DNA methylation, and gene expression into RC-2 sponsored frailty research, and c) develop improved access to human and/or animal biological samples and phenotypic data for needed for additional frailty research. This next stage of goals and advances will enable RC-2 to continue to support the most rigorous human genetic studies related to frailty while at the same time enable it to expand its scope to support studies of molecular pathways identified in genetics studies related to human frailty.